MR & Optical Diagnosis of Mitochondrial Metabolism and Dysfunction

描述（由申请人提供）：该申请基于我们最近的创新，涉及磁共振（MRS）和光学（OS）光谱方法的新组合，用于研究人类肌肉中的线粒体能量学。肌肉为线粒体缺陷提供了一个独特的窗口，线粒体缺陷是越来越多的代谢和退行性疾病（如糖尿病、神经变性和衰老）的中心。在这个竞争性的更新中，我们使用双OS/MRS光谱方法应用于骨骼肌来开发诊断程序，以识别线粒体功能缺陷。拟议的研究建立在该基金任期内取得的进展的基础上，这些进展导致了两项关键成就：1)用于测量化学含量和产生能量通量的动力学的OS/MRS组合策略；2)新的光学分析工具，为体内的可见光谱开发打开了道路。这一进展导致了Oz摄取的第一个定量测量，结合ATP通量，在体内无创地测量线粒体偶联。目标1扩展了线粒体！功能测量和利用我们的能力，利用可见光谱来开发基于细胞色素aas含量的线粒体容量测量。为了实现这一目标，我们将开发新的分析方法，将光谱学扩展到可见波长。Aim #2结合了新的光学和MRS方法来测定体内细胞和血管氧合。一种新的光学波长移分析结合MRS定量得到细胞氧合（[氧-Mb]/总[Mb]）和血液氧合（[氧-Hb]/总[Hb]）。这些氧合测量有可能揭示血管功能障碍，以及校准我们的氧摄取测定。目标#3提出设计、制造和实现一种多模态仪器，该仪器将光学光谱与交错、多核1H和31P MR光谱相结合。该仪器使用目标1和目标2中的技术进步，允许新的测量和增加的信噪比，这将允许在<90分钟的单次会话中研究人类肌肉中的线粒体功能。Aim #4将这种诊断工具转化为衰老，衰老伴随着明显的线粒体功能障碍，是对国民健康相当重要的一种疾病。在临床可行的会议上进行这种完整分析的能力将为代谢和退行性疾病功能障碍的性质和程度提供独特的诊断探针。完成该项目后，我们将能够将我们的工具转换为标准宽孔3T或其他用于临床环境的人体磁铁。

DESCRIPTION (provided by applicant): This application builds on our recent innovations involving a novel combination of magnetic resonance (MRS) and optical (OS) spectroscopic approaches for studying mitochondrial energetics in human muscle. Muscle provides a unique window on the mitochondrial defects that are at the center of a growing number of metabolic and degenerative diseases (e.g., diabetes, neurodegeneration and aging). In this competing renewal, we use the dual OS/MRS spectroscopy approach applied to skeletal muscle to develop diagnostic procedures for identifying defects in mitochondrial function. The proposed studies build on progress made over the tenure of this grant that have led to two key achievements: 1) a combined OS/MRS strategy for measuring chemical content and dynamics that yield energy fluxes and 2) new optical analytical tools that open the visible spectrum for exploitation in vivo. This progress has led to the first quantitative measurement of Oz uptake, which combined with ATP flux, measures mitochondrial coupling non-invasively in vivo. Aim #1 expands on this mitochondria! functional measurement and capitalizes on our ability to use the visible spectrum to develop a measurement of mitochondrial capacity based on cytochrome aas content. To achieve this, we will exploit new analytical methods that permit extending our optical spectroscopy into the visible wavelengths. Aim #2 combines new optical and MRS methods to determine cellular and vascular oxygenation in vivo. A novel optical wavelength shift analysis combined with quantification by MRS yields cellular oxygenation ([oxy-Mb]/total [Mb]) and blood oxygenation ([oxy-Hb]/total [Hb]). These oxygenation measurements have the potential to reveal vascular dysfunction, as well as calibrate our O2 uptake determinations. Aim #3 proposes to design, fabricate and implement a multimodal apparatus that will integrate optical spectroscopy with interleaved, multinuclear 1H and 31P MR spectroscopy. This apparatus uses the technological advances in Aims #1 and #2 to permit new measurements and increased signal-to- noise that will allow studies of mitochondrial function in human muscle in a single session of <90 min. Aim #4 translates this diagnostic tool to aging, which is accompanied by significant mitochondrial dysfunction and is a malady of considerable importance to the health of the nation. The ability to conduct such a complete analysis in a clinically feasible session will provide a unique diagnostic probe of the nature and extent of dysfunction in metabolic and degenerative disorders. Upon completion of this project we will be in position to translate our tools to standard wide bore 3T or other human magnets for use in a clinical setting.